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Published on: February 20, 2017
Landscape of Microsatellite Instability Across 39 Cancer Types
Russell Bonneville1, Melanie A Krook1, Esko A Kautto1
1The Ohio State University, Columbus, OH.
Purpose:
Microsatellite instability (MSI) is a pattern of hypermutation that occurs at genomic microsatellites and is caused by defects in the mismatch repair system. Mismatch repair deficiency that leads to MSI has been well described in several types of human cancer, most frequently in colorectal, endometrial, and gastric adenocarcinomas. MSI is known to be both predictive and prognostic, especially in colorectal cancer; however, current clinical guidelines only recommend MSI testing for colorectal and endometrial cancers. Therefore, less is known about the prevalence and extent of MSI among other types of cancer.
Methods:
Using our recently published MSI-calling software, MANTIS, we analyzed whole-exome data from 11,139 tumor-normal pairs from The Cancer Genome Atlas and Therapeutically Applicable Research to Generate Effective Treatments projects and external data sources across 39 cancer types. Within a subset of these cancer types, we assessed mutation burden, mutational signatures, and somatic variants associated with MSI.
Results:
We identified MSI in 3.8% of all cancers assessed-present in 27 of tumor types-most notably adrenocortical carcinoma (ACC), cervical cancer (CESC), and mesothelioma, in which MSI has not yet been well described. In addition, MSI-high ACC and CESC tumors were observed to have a higher average mutational burden than microsatellite-stable ACC and CESC tumors.
Conclusion:
We provide evidence of as-yet-unappreciated MSI in several types of cancer. These findings support an expanded role for clinical MSI testing across multiple cancer types as patients with MSI-positive tumors are predicted to benefit from novel immunotherapies in clinical trials.
Insights
Microsatellite instability (MSI) is now identified in 27 cancer types, not just colorectal and endometrial. This discovery supports broader clinical MSI testing for potential immunotherapy benefits in various cancers.
Area of Science:
- Genomics
- Oncology
- Cancer Research
Background:
- Microsatellite instability (MSI) is a hypermutation pattern caused by DNA mismatch repair defects.
- MSI is well-characterized in colorectal, endometrial, and gastric cancers, impacting prognosis and treatment prediction.
- Current clinical guidelines primarily recommend MSI testing only for colorectal and endometrial cancers, limiting knowledge in other tumor types.
Purpose of the Study:
- To investigate the prevalence and extent of MSI across a wide range of cancer types beyond those currently tested.
- To identify novel cancer types exhibiting MSI and characterize their associated mutational landscape.
Main Methods:
- Analysis of whole-exome data from 11,139 tumor-normal pairs across 39 cancer types using the MANTIS MSI-calling software.
- Assessment of mutation burden, mutational signatures, and somatic variants in MSI-positive tumors.
- Utilized data from The Cancer Genome Atlas, Therapeutically Applicable Research to Generate Effective Treatments projects, and external sources.
Main Results:
- MSI was identified in 3.8% of assessed cancers, present in 27 distinct tumor types.
- Notably, MSI was found in adrenocortical carcinoma (ACC), cervical cancer (CESC), and mesothelioma, where it was previously undescribed.
- MSI-high ACC and CESC tumors exhibited significantly higher average mutational burden compared to their microsatellite-stable counterparts.
Conclusions:
- This study reveals previously unrecognized MSI in several cancer types, expanding the known landscape of this genomic alteration.
- Findings advocate for an expanded role of clinical MSI testing across multiple cancer types.
- Patients with MSI-positive tumors may benefit from emerging immunotherapies currently in clinical trials.
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